Macromolecular MRI contrast agents based upon dendrimers obviate many of the deficiencies of serum albumin or linear polymer based MRI contrast agents of comparable size. This is due to the iterative polymeric synthesis by which they are created that then promotes a controlled size and shape of the dendrimer concomitantly generating the means for reproducible chemistry that is key to the clinical translation of such agents. To create MRI contrast agents with dendrimers, the terminal primary amines of dendrimers are modified with chelated Gd(III) developed in our laboratories. Historically, these reagents were shown to possess a molar relaxivity 6 times that of Magnevist, the currently approved MRI contrast agent. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained with PAMAM and polypropyleneimine or DAB dendrimer based agents. Past studies established that macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting fundamental criteria: generation (MW &size), core elements (lipophilicity &charge), PEG conjugation (prolong circulation and minimize liver and other organ uptake), lysine co-administration (renal clearance), and conjugation to targeting vectors (molecular targeting). PAMAM based agents have imaged murine tumor vasculature accurately at the 200 micron scale. DAB based agents have selective properties wherein reverse contrast images of 0.3 mm metastatic liver tumors were detected. These dendrimer based agents have also been selectively targeted, not only by conjugation to antibodies, but by other vectors, such as avidin to deliver exceptionally high levels of Gd(III) into disseminated intraperitoneal ovarian cancer tumor. This study done in conjunction with an optical imaging agent runs in parallel with our creation of multi-modality dendrimer based imaging agents. The incorporation of a NIR optical imaging dye into the MRI agent to add an enhanced level of sensitivity to complement the resolution of the MRI imaging provided an additional level of sensitivity for the imaging of lymphatics and sentinel nodes that can be envisioned as being translated to an intraoperative scenario wherein MRI imaging and mapping would supplement real-time surgical intervention and excision of malignancy. While the chemistry established the ability to create such macromolecular agents, the imaging resulted in compromised targeting which defined that these agents require very careful systematic investigation combined with equally careful defined characterization. Lastly, new chelation chemistry for conjugation of Gd(III) complexes to dendrimer has been prompted by the need to re-invent this field moving it from aqueous chemistry back to organic phase solvents to enhance both characterization and consistency of yields. This chemistry has also evolved out of the need for specialized analogs of established bifunctional chelation agents to address the development of site-specific conjugation chemistry required for actively targeted dendrimer based imaging agents e.g, maleimides targeting a unique thiol residue, or agents functionalized with alkyne and azide groups for click chemistry conjugation strategies. In parallel to this effort, the very recent impact on NFS related Gd(III) toxicity of less than adequately stable MRI contrast agents that had prompted a complete halt of projects with an application of new directionality in the choice of bifunctional chelating agent at the heart of all of these studies has resulted in redirection of all such projects with the use of DOTA as the bifunctional chelating agent, however with the Gd(III) complex pre-formed prior to conjugation to all targeting vectors. While this effort was put into place over the past 2 years, all of the MR contrast projects have now migrated to the exclusive use of a pre-complexation of the Gd(III) conjugate strategy using DOTA to eliminate a characterization complexity resulting from the creation of exceedingly difficult to characterize mixtures of product that limited reproducibility of agents that would have complicated translation of these agents into clinical use. Results from the studies to validate this transformation have revealed that not only can such a strategy be successfully employed despite warnings of probably lowered solubility (not true), but that far greater molar relaxivity can be achieved by this means. We have reported a 5-fold enhancement over the prior technology while concurrently decreasing the actual physical amount of Gd(III) conjugated to the dendrimer by 65%. The impact of this result should reach across to all macromolecular MR contrast agents regardless of platform to fully address safety, characterization, and reproducibility thereby furthering an entire fields potential for clinical translation of such agents. The exquisite advantages of the dendrimer based agents over low molecular weight agents continue to be very clearly demonstrated. In parallel to this improvement to abrogate toxicity concerns that has resulted in superior dendrimer based agents, the collaboration with NINDS developing a surrogate marker for CED of chemotherapeutic drugs using an albumin core platform was terminated vs. continuing with the less safe DTPA chemistry. While regrettable, the Chemistry Section always opts to pursue fundamentally sound and reproducible science and chemistry that permits advancing technology into the clinic in the safest format possible using a safe agent as opposed to knowingly participating in studies that might employ an unsafe agent. Regardless of this disappointment, the Chemistry Section continued the investigation independently to validate the use of the above strategy and a report has been submitted for publication on those results. The US patent covering this technology was issued last year and these new results, particularly those related to its application to an albumin core, should prove to make it yet more valuable to HHS and should also contribute to translation of this technology into the clinic. Studies of MRI and other imaging modality agents in collaboration with the Molecular Imaging Program have unfortunately been terminated due to a lack of cooperation and access to instrumentation residing therein in what was to be a resource for all NCI researchers despite agreements to the contrary. However, established collaborations with Radiology, CC, the PET Dept, CC, NIMH, and extramural researchers continue to be fruitful.